In this study, researchers want to learn about the safety of drug BAY2701439 and how well the
drug works in patients with advanced cancer that has the protein HER2 (Human Epidermal growth
factor Receptor 2) and cannot be cured by currently available treatment options. The study
will include patients with HER2 expressing breast, gastric (stomach) or gastroesophageal
(stomach and esophagus) cancer, as well as other cancers that have HER2. Researchers want to
find the best dose of BAY2701439 for patients and look at the way the body absorbs,
distributes and excretes the drug.
The study drug is a type of therapy called a 'targeted alpha therapy' which uses an antibody
to deliver a radioactive particle to cancer cells. BAY2701439 contains thorium-227 which
emits radiation (a lot of energy that moves from one place to another with damaging effects).
The thorium-227 in the drug is attached to an 'antibody' (large protein) that specifically
binds to HER2 on the cancer cells and will emit its radiation in the form of alpha particles.
The alpha particles are expected to damage the tumor cells and cause them to die, but spare
surrounding tissue as alpha particles travel only very short distances in the body. This is
the first study in humans for drug BAY2701439. Patients participating in this study will
receive the drug by injection every 6 weeks a maximum 6 times. Observation after treatment
last up to 3 years.
Inclusion Criteria:
- Male or female participants at least 18 years of age on the day of signing informed
consent.
- Participants must meet the study phase-specific disease requirements:
Dose escalation:
Pathologically documented, HER2-expressing (IHC3+, 2+, or 1+ and/or ISH+), unresectable
locally advanced or metastatic gastric, gastroesophageal, or breast cancer that has
relapsed after standard treatment options, or for which no standard treatment is available.
Participants with gastric or gastroesophageal cancer must not have had prior definitive
radiotherapy. Participants in the dose escalation cohorts must have evaluable disease by
RECIST 1.1, assessed by local imaging.
- Dose expansion: Group A: Pathologically documented unresectable, locally advanced or
metastatic breast cancer with HER2 overexpression or amplification (IHC3+ or IHC2+/ISH+)
that has relapsed that has relapsed after standard treatment options, or for which no
standard treatment is available.
Group B: Pathologically documented unresectable locally advanced or metastatic breast
cancer with HER2 low expression (IHC2+/ISH-, IHC1+/ISH-, or IHC1+/ISH untested) that has
relapsed after standard treatment options, or for which no standard treatment is available.
Group C: Pathologically documented, unresectable locally advanced or metastatic carcinomas
other than breast cancer with HER2 overexpression or amplification/mutation (IHC3+ or
IHC2+/ISH+), that has relapsed after standard treatment options or for which no standard
treatment is available.
Participants in the dose expansion cohorts must have measurable disease by RECIST 1.1,
assessed by local imaging.
- Availability of fresh or archival tumor samples - archival tumor samples obtained
after disease progression on the most recent anti-cancer treatment may be accepted;
those obtained prior to the last anti-cancer treatment may be accepted, upon agreement
between the Sponsor and the Investigator.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
- Life expectancy of at least 6 months, as estimated by the Investigator.
- Adequate bone marrow, hepatic, and renal function, as assessed by the following
laboratory requirements, to be conducted within 28 days before start of BAY2701439
administration:
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1500/mm*3
- Platelet count ≥ 100,000/mm*3
- Total bilirubin ≤ 1.5 X the upper limit of normal (ULN), except if confirmed
history of Gilbert's disease
- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ˂ 2.5 x ULN
(≤ 5 x ULN for participants with liver involvement)
- Participants on a stable dose of anti-coagulation therapy will be allowed to
participate if they have no sign of bleeding or clotting, and Prothrombin
time/International normalized ratio (PT/INR) and aPTT test results are compatible
with the acceptable benefit-risk ratio at the Investigator's discretion
- Serum creatinine ≤ 1.5 x ULN and glomerular filtration rate (GFR)≥ 45 mL/min/1.73
m*2, according to the Modified Diet in Renal Disease (MDRD)abbreviated formula.
- A negative serum pregnancy test in women of childbearing potential (WOCBP) performed
within 7 days before the start of BAY2701439 administration. Women and men of
reproductive potential must agree to use highly effective methods of contraception,
when sexually active, during the time period between signing the informed consent form
until at least 6 months after the last administration of BAY2701439.
- Male and/or female who meet the requirements for contraception and breastfeeding as
follows:
Male participants: A male participant must agree to use highly effective contraception
during the intervention period and for at least 6 months after intervention and refrain
from donating sperm during this period.
Female participants: A female participant is eligible to participate if she is not pregnant
(confirmed by a negative serum pregnancy test within 7 days of first study treatment), not
breastfeeding, or is not a woman of childbearing potential.
Women of childbearing potential (WOCBP) must agree to use highly effective contraception
during the intervention period and for at least 6 months after the last dose of study
treatment.
Contraceptive use by men or women should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
- Capable of giving signed informed consent which includes compliance with the requirements
and restrictions listed in the informed consent form (ICF) and in this protocol
Exclusion Criteria:
- Impaired cardiac function or clinically significant cardiac disease (i.e. congestive
heart failure (CHF) New York Heart Association (NYHA) Class II, III or IV).
- Left ventricular ejection fraction (LVEF) < 50% (as measured at screening by
echocardiogram).
- History or concurrent condition of interstitial lung disease/pneumonitis or severely
impaired pulmonary function.
- Participants known to be affected by genetic defects linked to radiation
hypersensitivity, such as ataxia-telangiectasia (A-T; Online Mendelian Inheritance in
Man [OMIM] #208900) and A-T-like disorder (meiotic recombination 11 homolog [MRE11]),
Nijmegen breakage syndrome (OMIM #251260) and Nijmegen breakage Syndrome-like disorder
(RAD50), Fanconi anemia (OMIM #227650), DNA ligase IV deficiency (OMIM #606593),
RIDDLE syndrome (RNF168), radiosensitive severe combined immunodeficiency (RS-SCID),
DNA-PK radiosensitive combined immunodeficiency (DNA-PK-RS-SCID), Cornelia de Lange
syndrome.
- History of Myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia
(t-AML) or with features suggestive of MDS/AML.
- Infections of Common terminology criteria for adverse events (CTCAE) version 5.0 Grade
2 not responding to therapy or active clinically serious infections of CTCAE Grade >2.
- History of hypersensitivity or severe infusion related reaction to any
Trastuzumab-containing drug (e.g. trastuzumab, T-DM1) or any other ingredients
contained in BAY2701439.
- Chemotherapy, experimental cancer therapy, biologic therapy or immunotherapy within 4
weeks before start of BAY2701439 administration. Start of study treatment is allowed
in shorter timeframes provided 5 half-lives of the prior drug(s) have elapsed before
the start of BAY2701439 administration. Previous high-dose chemotherapy needing
hematopoietic-stem-cell-rescue is prohibited.
